The well-recognized immunosuppressive effects of both alcohol and HIV infection highlight the importance of understanding the interactions between these two immunocompromising factors. Alcohol abuse increases host susceptibility to infections by impairing innate and specific limbs of the immune system. HIV exerts its pathogenic effects primarily through its interaction with and subsequent incorporation into the genome of CD4+ cells to include T helper lymphocytes, mononuclear phagocytes (particularly tissue-resident macrophages), and microglial cells. The impact of alcohol consumption on susceptibility to HIV infection and progression of HIV infection once established is unknown. Epidemiological evidence implicating an interaction between alcohol use and susceptibility to, or progression of, HIV infection is conflicting. Because such an interaction might be masked by the complex nature and variability of HIV disease and changing behavior of those infected, we are proposing to determine the impact of alcohol of simian immunodeficiency virus (SIV) infection of rhesus monkeys, a well characterized and accepted nonhuman primate model of HIV infection. The long term goal of this project is to define alcohol's impact on the progression and sequelae of SIV infection as it relates to the primary infection as well as the development of secondary opportunistic infections, particularly as they impact pulmonary host defense. In this project we will examine the hypothesis that alcohol will exacerbate the SIV-induced immunodeficient state by promoting viral replication in CD4+ lymphocytes and mononuclear phagocytes which would potentially result in a further compromise of effector capabilities of the monocyte/macrophage system. This will be accomplished by addressing the following Specific Aims 1) To determine the direct effect (ex vivo) of alcohol on the spontaneous and elicited cytokine responses by alveolar macrophages and blood obtained from uninfected and SIV-infected rhesus monkeys at known stages of disease; 2) to examine the direct effect (ex vivo) of alcohol on SIV infection of blood lymphocytes and alveolar macrophages obtained from uninfected rhesus monkeys receiving or not receiving alcohol (in vivo) during the previous months; 3) to examine the sub-chronic effect of in vivo alcohol administration on viral burden in SIV-infected rhesus monkeys. These studies will provide important and novel information on the potential role of alcohol on progression of HIV infection to AIDS. In addition, the data and experience gained in this highly relevant and pertinent model of HIV/AIDS will be essential to the design and successful execution of future studies on the interaction between alcohol and HIV infection with respect to disease progression to AIDS and the development of